Erectile dysfunction remedies containing prostaglandin derivatives as the active ingredient

ABSTRACT

Therapeutic agents for erectile dysfunction containing as the active ingredient prostaglandin derivatives of formula (I)  
                 
 
     (wherein, R 1  is ethyl or n-2-propenyl.), esters thereof, nontoxic salts thereof, or cyclodextrin clathrate compounds thereof.  
     The compounds of the formula (I) are useful for the treatment of erectile dysfunction.

TECHNICAL FIELD

[0001] The present invention relates to a therapeutic agent for erectiledysfunction. More particularly, it relates to a therapeutic agent forerectile dysfunction containing as the active ingredient prostaglandinderivatives of the formula (1)

[0002] (wherein, R¹ is ethyl or n-2-propenyl.),

[0003] esters thereof, nontoxic salts thereof or cyclodextrin clathratecompounds thereof.

BACKGROUND ART

[0004] Male sexual dysfunction, in particular erectile dysfunction, isattributed to various causes such as aging, operation of prostate gland,injury of nerve cord, and diabetes. However, what is common in thesecauses is that a decrease of blood flow into the corpus cavernosum penisis the direct cause. As one of methods of treating it, administration ofa vasodilator such as prostaglandin E₁ (hereinafter abbreviated as PGE₁)has been considered effective (DICP—The animal of Pharmacotherapy, 5,363 (1991)). However, PGE₁ has problems that it is attended with pain(angialgia) upon administration, that the drug itself is unstable and soforth.

[0005] On the other hand, it has been found that prostaglandin E₂(hereinafter, abbreviated as PGE₂) that has oxytocic effect also hasutillity for erectile dysfunction. This has made it unclear whether ornot the erectile dysfunction improving action of PGE₁ is simply based onits vasodilating action (WO93/00894).

[0006] PGE₂ is known to be as a metabolite in the cascade of arachidonicacid and have various activities such as cytoprotection, oxytociceffect, algesic effect, promotion of vermicular movement of digestivetract, arousal effect, supression of gastric-acid secretion, hypotensiveactivity, and diuretic action.

[0007] Studies in recent years have revealed that PGE₂ receptores havesubtypes that play different roles from each other. Currently knownsubtypes are roughly classified into four groups called EP₁, EP₂, EP₃,and EP₄, respectively (Negishi M. et al, J. Lipid Mediators CellSignaling 12, 379-391 (1995)). Examination of separate roles of thesereceptors with compounds that bind to specific receptors and findingcompounds not to bind any other subtype receptors has made it possibleto obtain drugs having less side effects.

[0008] Recently, an application disclosing that the compounds having anω-chain of PGE₂ modified with a hydroxyl group have an effect onerectile dysfunction equivalent to that of PGE₁ and are less irritatinghas been laid open to public inspection. It also describes that thecompounds disclosed therein are EP₂-specific (cf., WO99/02164).

[0009] Furthermore, the compounds used in the present inventionrepresented by the formula (I) are the compounds described in Example 17and 17(1) in the specification of Europian Patent Publication No.860430.

SUMMARY OF THE INVENTION

[0010] The inventors of the present invention have made extensive studywith a view to finding compounds that have erectile dysfunctionimproving effect equivalent to or higher than PGE₁ and 19-hydroxy-PGE₂and have less side effects. As a result, they have found that thecompounds used in the present invention of the formula (I) meet theobject and attained the present invention.

[0011] The compounds used in the present invention specifically bind tosubtype EP₂ receptor but do not almost bind to other subtypes EP₁, EP₃,EP₄ and the like. Therefore, the compounds used in the present inventiondo not have algesic action which may be attributed to EP₁, oxytocicaction which may be attributed to EP₃, immunoregulation effect which maybe attributed to EP₄, and the like and hence they are drugs free ofinfluences on these actions. In addition, as will be apparent from theexperiments shown hereinbelow, the compounds used in the presentinvention exhibit effects equivalent to those of PGE₁ and19-Hydroxy-PGE₂ whose usefulness has already been recognized, so thatthey are useful as therapeutic agents for erectile dysfunction havingless side effects. Furthermore, the compounds used in the presentinvention are applicable to improving of female sexual function.Although the compounds used in the present invention of the formula (I)are specifically disclosed in the specification of Europian PatentPublication No. 860430, it has not been known that the compounds areeffective to erectile dysfunction and this is the first time that it wasfound.

DISCLOSURE OF THE INVENTION

[0012] The present invention relates to a therapeutic agent for erectiledysfunction. More particularly, it relates to a therapeutic agent forerectile dysfunction containing as the active ingredient one or morecompounds selected from prostaglandin derivatives of the formula (I)

[0013] (wherein, R¹ is ethyl or n-2-propenyl.),

[0014] nontoxic salts thereof or cyclodextrin clathrate compoundsthereof.

[0015] [Esters]

[0016] The compounds used in the present invention of the formula (I)can be converted into esters by a known method. Since esterificationincreases stability and absorbability of the compounds, the esters areuseful as pharmaceutical preparations. Preferred esters include alkylesters. C1-4-Alkyl esters are more preferred, with methyl ester beingmost preferred.

[0017] [Salts]

[0018] The compounds used in the present invention of the formula (I)can be converted into corresponding salts by a known method. The saltsare preferably nontoxic and water-soluble salts. Suitable salts includealkali metal (potassium, sodium, etc.) salts, alkaline earth metal(calcium, magnesium, etc.) salts, ammonium salts, and pharmaceuticallyacceptable organic amine (tetramethylammonium, triethylamine,methylamine, dimethylamine, cyclopentylamine, benzylamine,phenethylamine, piperidine, monoethanolamine, diethanolamine,tris(hydroxymethyl)amine, lysine, arginine, N-methyl-D-glucamine, etc.)salts. Preferred salts include lysine salts. In addition, the compoundsused in the present invention of the formula (I) can be converted intohydrates by a known method.

[0019] [Clathrate Compounds]

[0020] The compounds used in the present invention of the formula (I) oresters thereof can be converted into cyclodextrin clathrate compounds bythe method described in the specifications of GB 1,351,238 or GB1,419,221 by using α-, β- or γ-cyclodextrin or mixtures thereof. Sinceconversion into cyclodextrin clathrate compounds increases stability andsolubility in water of the compounds, the cyclodextrin clathratecompounds are convenient when they are used as drugs.

[0021] [The Method for the Preparation of Compounds of the Formula (I)]

[0022] The compounds used in the present invention of the formula (I),esters thereof or nontoxic salts thereof can be prepared by the methoddescribed in the specification of Europian Patent Publication No.860430.

BEST MODE FOR CARRYING OUT THE INVENTION

[0023] That the compounds used in the present invention of the formula(I) can be used for the therapy of erectile dysfunction was confirmed bythe following pharmacological experiments.

EXAMPLE 1 Corpus Cavernosum Relaxation Activity in Cats

[0024] [Pharmacological Examination]

[0025] Under anesthesia with urethane, penis of five cats (hybrid,weight about 3.5 kg) was removed. In the krebs solution, a corpuscavernosum was isorated, quartered and suspended with the tention of 200mg in the Magnus tube. 10 μM norepinephrine was added and the tissue wasconstricted. Then the stable contraction was checked. After the additionof norepinephrine, (5Z, 9β, 11α,13E)-17,17-propano-11,16-dihydroxy-9-chloro-20-norprosta-5,13-dienicacid·lysine salt (compound A) and (5Z, 9β, 11α,13E)-17,17-propano-11,16-dihydroxy-9-chloroprosta-5,13,19-trienic acid(compound B), which are the compounds of the formula (I), were addedrespectively and the changes of the contraction were measured. Ascontrols, PGE₁ and 19-hydroxy-PGE₂ were used. Each compounds weredisolved in DMSO and used. The contraction induced by 10 μMnorepinephrine was considered as 100% and the percentages of therelaxation rate were calculated. These results were showed on Table 1.TABLE 1 Corpus cavernosum Adoministered Dose relaxation rate Compounds(μM) (%) Compound A 0.1 26.8 ± 4.2 Compound A 1.0 35.2 ± 2.8 Compound B0.1 18.1 ± 4.8 Compound B 1.0 36.8 ± 4.2 PGE₁ 0.1 21.3 ± 2.3 PGE₁ 1.035.5 ± 5.0 19-hydroxy-PGE₂ 0.3 20.0 ± 4.2 19-hydroxy-PGE₂ 1.0 27.2 ± 4.7

[0026] Numeric values are Means±SE.

[0027] [Consideration]

[0028] The compounds used in the present invention of the formula (I)(compound A and B) elicited dose-dependent relaxasions of corpuscavernosum and its intensity were at the same level as PGE₁. Thecontraction activity of the compounds used in the present invention ofthe formula (I) (compound A and B) were 3 or 10 times as potent as thatof 19-hydroxy-PGE₂.

EXAMPLE 2 Corpus Cavernosum Relaxation Activity in Human

[0029] [Pharmacological Examination]

[0030] The samples of the human corpus cavernosum taken at the time ofoperative treatment in agreement of the patient were suspended with thetention of 500 mg in the Magnus tube fulled by glucose-added Krebsbuffer. The 10⁻⁵M (10 μM) noradrenalin-induced contraction reaction,acetylcholine-induced relaxation reaction andelectrostimulation(EFS)-induced contraction reaction were checked andthe samples responded normaly were used in the experiment. It wasreconstricted by 10 μM noradrenalin, the compound A used in the presentinvention of the formula (I) (n=4), the compound B used in the presentinvention of the formula (I) (n=5) or PGE1 (n=5), which were disolved byDMSO, were added cumulatively and the relaxation reacton was recorded onthe chart. The contraction induced by 10 μM noradrenaline was concideredas 100% and the percentage of the relaxation rate was calculated. Theseresults were showed on Table 2. TABLE 2 Corpus cavernosum AdoministeredDose relaxation rate Compounds (μM) (%) compound A 1.0 29.9 ± 13.7compound A 10 44.5 ± 12.6 compound B 1.0 25.0 ± 4.4  compound B 10 45.3± 4.5  PGE₁ 1.0 16.8 ± 7.2  PGE₁ 10 27.9 ± 8.8 

[0031] Numeric values are Means±SE.

[0032] [Consideration]

[0033] In human corpus carvenosum, the activity of compound A and B usedin the present invention of the formula (I) were 1.6 times as potent asthat of PGE₁, so they are useful for the treatment of erectiledysfunction.

[0034] [Toxicity]

[0035] It has been confirmed that the compounds used in the presentinvention of the formula (I) have sufficiently low toxicity and aresufficiently safe for use as pharmaceutical preparations. For example,the maximal tolerated dose of the compound A (lysine salts) in thecompound of the formula (I) was 30 mg/kg weight or more for ratintravenous administration.

INDUSTRIAL APPLICABILITY

[0036] The compounds used in the present invention of the formula (I)are useful for the treatment of erectile dysfunction. When used for theabove-mentioned purposes, usually the compounds used in the presentinvention of the formula (I), esters thereof, nontoxic salts thereof,and cyclodextrin clathrate compounds thereof are locally administered inparenteral forms. Use of them in the form of prodrug provides advantagessuch as elimination of irritation, improved absorption, improvedstability and the like.

[0037] The doses to be administered are determined depending upon age,body weight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment etc. In the humanadult, the doses per person are generally from 1 μg to 100 mg, by oraladministration, from once up to several times per day, and from 0.1 μgto 10 mg, by parenteral administration (preferably, percutaneousadministration, subcutaneous administration, perurethral administration,or intravenous administration) from once up to several times per day, orby continuous administration for from 1 hour to 24 hours per day intovein.

[0038] Of course, as described above, the dose may vary depending onvarious conditions, and in some cases an amount less than the amountdescribed above will suffice or in some cases, administration of anamount exceeding the above-mentioned range will be necessary.

[0039] When the compounds used in the present invention of the formula(I) are administered, they are used in the form of injection, externalpreparations such as ointments, patches for attaching to skin,suppositories and the like for parenteral administration.

[0040] The injection for parenteral administration according to thepresent invention includes sterile aqueous or nonaqueous solutions,suspensions and emulsions. The aqueous solutions and suspensionsinclude, for example, distilled water for injection and saline. Thenonaqueous solutions and suspensions include, for example, propyleneglycol, polyethylene glycol and plant oils such as olive oil, alcoholssuch as ethanol, Polysorbate 80 (registered trademark) and the like.Such compositions may further contain antiseptics, humectants,emulsifiers, dispersants, stabilizers, or auxiliaries such asdissolution auxiliaries (for example, glutamic acid and aspartic acid).These can be sterilized by filtration through a bacteria-retainingfilter, compounding of a germicide, or irradiation. These can besterilized by producing a sterile solid composition and sterilizingbefore use or they are dissolved in sterile distilled water forinjection or other solvents before they can be used.

[0041] Other compositions for parenteral administration in dude externalliquids, ointments, liniments, patches, and suppositories, eachcontaining one or more active ingredients.

[0042] The ointment may contain besides a base such as white vaseline,pH adjusters, surfactants, antiseptics, emulsifiers, dispersants,stabilizers, dissolution auxiliaries and so forth.

PREPARATION EXAMPLE 1 Freeze-Dried Products

[0043] After mixing the following components by a conventional method,the resulting solution was sterilized by a conventional method and 1 mlportions thereof were filled in vials, respectively, and freeze-dried bya conventional method to obtain 100 vials of injection containing each0.2 mg of the active ingredient. (5Z,9β,11α,13E)-17,17-propano-11,16-27.3 mg dihydroxy-9-chloro-20-norprosta- 5,13-dienic acid · lysine saltMannitol   5 g Distilled water  100 ml

PREPARATION EXAMPLE 2 Ointment

[0044] The following components were mixed by a conventional method and10 g portions thereof were filled in tubes, respectively, to obtain 100tubes of ointment containing each 0.2 mg per 1 g of the activeingredient. (5Z,9β,11α,13E)-17,17-propano-11,16- 273 mgdihydroxy-9-chloro-20-norprosta- 5,13-dienic acid · lysine salt Whitevaseline  1 kg

1. A therapeutic agent for erectile dysfunction containing as the activeingredient one or more compounds selected from prostaglandin derivativesof the formula (I)

(wherein, R¹ is ethyl or n-2-propenyl.), esters thereof, nontoxic saltsthereof or cyclodextrin clathrate compounds thereof.
 2. The therapeuticagent for erectile dysfunction as claimed in claim 1, wherein the activeingredient comprises(5Z,9β,11α,13E)-17,17-propano-11,16-dihydroxy-9-chloro-20-norprosta-5,13-dienicacid, lysine salt thereof, or a α-cyclodextrin clathrate compoundthereof.
 3. The therapeutic agent for erectile dysfunction as claimed inclaim 1, wherein the active ingredient comprises(5Z,9β,11α,13E)-17,17-propano-11,16-dihydroxy-9-chloroprosta-5,13,19-trienicacid, lysine salt thereof, or a α-cyclodextrin clathrate compoundthereof.